Delivery and administration of compositions using interventional catheters

ABSTRACT

Systems and methods for delivery of therapeutic and/or diagnostic compositions to an interventional site having diseased or newly treated tissue are provided. Integrated interventional catheter systems incorporating surfaces coated with a diagnostic or therapeutic composition, or ports for infusing a diagnostic or therapeutic composition prior to, during or following an interventional procedure are provided.

REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 12/742,903, filed Aug. 27, 2010, which was a national phase entryunder 35 U.S.C. 371 of PCT Intl' Patent Application No.PCT/US2008/0083690, filed Nov. 14, 2008, which claims priority to U.S.Application No. 60/988,001, filed Nov. 14, 2007. These relatedapplications are incorporated by reference herein in their entireties.

FIELD OF THE INVENTION

The present invention relates to the delivery and administration oftherapeutic and/or diagnostic compositions to treat diseased tissue. Theinvention relates, more particularly, to the delivery and administrationof therapeutic and/or diagnostic compositions prior to, during orsubsequent to an intervention, such as displacement or removal ofobstructions and partial obstructions from an internal lumen or cavityof a mammalian subject, and to interventional catheters for delivery ofsuch compositions.

BACKGROUND

Angioplastic techniques for creating and enlarging openings inobstructed or partially obstructed blood vessels by inflating a balloonor another device at or near the site of an occlusion using aninterventional catheter are well known and commonly employed. Materialforming the obstruction is typically compressed during angioplasty asthe vessel wall is stretched to enlarge the vessel lumen. An implantabledevice, such as a stent, may be placed at the site to maintain orimprove vessel patency. Restenosis of vessels following angioplasty andstent placement procedures is common and may require additionalinterventions. Drug-eluting stents were developed to retard or reducethe incidence and severity of restenosis and have been effective in manycircumstances.

Removal of diseased tissue, such as atherosclerotic plaque, thrombus andother types of obstructions and partial obstructions from internal bodylumens or cavities is also a well-established interventional technique.Numerous interventional catheters have been conceived and developed.Most of these systems require placement of a guiding catheter and guidewire prior to introduction of the interventional catheter and placementof the interventional catheter near the target operating site.Advanceable, rotating operating heads have been used to cut and/orabrade and/or ablate obstructions. Plaque excision devices thatincorporate cutting or scraping structures operating through a window orport, or having coring or helical screw structures that operate in arecessed opening, are also used. Aspirating catheters have been used toremove diffuse material, such as thrombus. Many of these prior artsystems incorporate aspiration or mechanical withdrawal systems toremove the obstructive material from the site. Some systems incorporateor are used in conjunction with mechanisms such as distal filters forpreventing obstructive material from circulating in the blood stream.

Other types of material removal systems, such as excimer lasers, highintensity focused ultrasound systems, RF systems, and the like have alsobeen devised and used. Although mechanical devices such as cutter-basedand mechanical removal devices and laser and ultrasound-based systemsare effective in removing diseased tissue from and opening lumensthrough blood vessels, it is difficult to prevent restenosis of thevessel following material removal. Thus, despite the many and variedtechniques used to prevent blood vessels from becoming occluded and thesuccessful removal of material and placement of implantable devices suchas stents, prevention of restenosis following the intervention remainsproblematic.

Many interventional devices have infusion systems that infuse liquidssuch as saline, imaging compositions, or therapeutic and/or diagnosticcompositions to a site of intervention prior to or during operation ofthe device. Delivery of therapeutic and/or diagnostic compositions insolution using conventional infusion protocols generally isn't effectivefor treatment of tissue at interventional sites in blood vessels becausethe infusate is rapidly diluted and carried away in the bloodstream. Foreffective therapy or diagnosis, the composition must generally remain incontact with and have an opportunity to interact with the diseased oraffected tissue. Delivery of therapeutic and diagnostic compositions tointerventional sites in the blood stream thus remains challenging.

Many systems have been conceived and developed for delivery oftherapeutic compositions to an interventional site. U.S. PatentPublication No. US 2005/0250672 describes a composition for restenosisprevention including an antihyperplastic composition. The compositionmay be applied to the outer surface of a catheter for delivery. U.S.Patent Publication No. US 2006/0020243 discloses balloon catheterscoated with lipophilic drugs. U.S. Pat. No. 6,939,320 discloses amedical device including an expandable substrate, such as a ballooncatheter, coated with a drug, and an expandable sheath positioned overthe substrate, the expandable sheath having at least one perforationthat is substantially closed when the substrate and the sheath are in acompressed state and substantially open when the substrate and sheathare expanded. The drug is thus able to pass through the sheath followingexpansion of the substrate and sheath.

U.S. Pat. No. 6,997,898 discloses a catheter provided with multipleinflatable balloons that, when inflated, create closed delivery pocketsfor delivery of compositions to a defined space. PCT InternationalPublication No. WO 2005/055800 provides a method for exposing theluminal wall of a blood vessel to a substance by deploying adrug-eluting polymer film inside the lumen of the blood vessel during orfollowing angioplasty.

U.S. Pat. No. 5,843,033 discloses an inflatable balloon catheter havinga plurality of conduits in fluid communication with a plurality ofapertures on the outer surface of the balloon, whereby medications aretransferred from the conduits into a surrounding vessel followinginflation of the balloon. U.S. Pat. No. 6,210,392 provides a deviceincluding an inflatable balloon mounted on a catheter, the balloonhaving a plurality of dispensers that extend outwardly from the balloonand are in fluid communication with a fluid source. Following deliveryof the balloon to a treatment area in a vessel, the balloon is inflatedto embed the dispensers in the vessel wall and fluid is introduced intothe treatment area. U.S. Patent Publication No. US 2004/0098014discloses a balloon angioplasty device having a plurality of cuttingelements, such as microneedles, provided on the outer surface of theballoon. The microneedles enhance dilation of an artery and may beemployed to deliver a drug to a cutting region.

U.S. Pat. No. 5,196,024 discloses a balloon catheter having cuttingedges located parallel to the longitudinal axis of the balloon that makelongitudinal cuts in a vessel wall. During delivery, the cutting edgesare covered by folds of the deflated balloon, thereby minimizing injuryto the vessel wall. U.S. Pat. No. 5,320,634 describes an angioplastydevice comprising an inflatable balloon having a plurality ofatherotomes mounted on its outer surface, the balloon being mounted on acatheter.

SUMMARY

The present invention provides systems and methods for effectivelydelivering therapeutic and/or diagnostic compositions to a site in abody lumen or cavity. In some embodiments, delivery of therapeuticand/or diagnostic composition(s) is provided in conjunction with aprocedure employing an interventional catheter for delivering a devicesuch as a balloon, or an implantable device such as a stent, to a sitein a body lumen or cavity. In alternative embodiments, delivery oftherapeutic and/or diagnostic composition(s) is provided in conjunctionwith a procedure involving an interventional catheter that removesunwanted material from a site in a lumen or cavity using a mechanicalmechanism such as a cutter assembly, or a scraping mechanism or coringor helical screw mechanism, or employing a different ablative mechanismsuch as a laser, a high frequency ultrasound source, a radio frequency(RF) source, or a thermal or electrical source, or the like. Suchsystems and methods may be effectively employed to remove unwantedmaterial from a treatment site in a body lumen and to delivertherapeutic and/or diagnostic composition(s) to the treatment site priorto, during and/or subsequent to the removal of unwanted material fromthe site.

In one embodiment, a delivery device of the present invention may beprovided as a stand-alone delivery device, while in alternativeembodiments, delivery devices of the present invention may beincorporated into or integrated with interventional devices such asinterventional catheters used in angioplastic techniques, for placementof implantable devices, or for material removal (e.g., atherectomy andthrombectomy). In embodiments in which the delivery device is providedas a stand-alone device, a fluid delivery mechanism is generallyprovided at a distal end of an infusion lumen that may be connected toan infusate source. The delivery device may be designed for use intandem with or as a rapid exchange device in connection with anotherinterventional device and may share certain control and/or powerfunctions with the interventional device. Alternatively, the deliverydevice may be incorporated into and integrated with an interventionaldevice, such as an interventional catheter, that additionally providesmechanisms for angioplastic techniques, for placement of implantabledevices, or for removal of unwanted material from a body lumen orcavity.

Delivery systems of the present invention generally provide a surface ora structure that contacts tissue at the site of intervention. Differentmechanisms may be used for delivery of therapeutic and/or diagnosticcompositions. In one embodiment, the delivery system of the presentinvention employs a device, such as an inflatable device, that is coatedwith a therapeutic and/or diagnostic composition. Various formulationsfor coating or impregnating or associating compositions with surfaces,providing release or uptake of the compositions are known and may beused with methods and systems of the present invention. An inflatabledevice may be guided to a desired treatment site in a collapsedcondition and then inflated at the treatment site to contact tissuebeing treated and/or diagnosed. The therapeutic and/or diagnosticcomposition(s) are contacted to and taken up by the tissue rather thanbeing diluted and carried away by the bloodstream or other fluids inproximity to the site.

The inflatable delivery device may incorporate blades or pins or othertypes of surface protuberances or abrasives or rough edges on its outersurface that produce fissures or channels or discontinuities in thetissue as the device contacts tissue to enhance uptake of thetherapeutic and/or diagnostic composition(s). The inflatable deliverydevice may additionally or alternatively incorporate pores or portsthat, upon inflation, allow passage of fluids containing therapeuticand/or diagnostic substances. The inflatable device may additionally oralternatively incorporate structures such as micro-needles that providechannels for delivery of fluids containing therapeutic and/or diagnosticsubstances. The microneedles may penetrate tissue at a site ofintervention when the inflatable device is inflated to deposittherapeutic and/or diagnostic fluids under the exposed surface or withintissue at the site of the intervention. Inflation of the device may bemonitored and adjusted to provide a desired degree of penetration. Theinflatable device is generally maintained in a stationary conditionduring inflation and contacting of its outer surface(s) to the treatmentsite but, in alternative embodiments, the inflatable device may berotated and/or translated and/or vibrated during inflation and/or duringcontacting of its outer surface(s) and/or the structure(s) associatedwith the inflatable device to the treatment site.

In another embodiment, a delivery system of the present invention mayemploy tissue contacting and/or penetration structures that may be movedin relation to the tissue to produce fissures or channels ordiscontinuities in the tissue and thereby enhance the uptake oftherapeutic and/or diagnostic compositions at the site of intervention.According to one embodiment, tissue contacting and/or penetrationstructures may be provided on an interventional device, such as on anoperating head or a cutting blade of an interventional device. In thisembodiment, as the operating head and/or cutting blade(s) are moved(e.g. rotated and/or translated) during an interventional procedure, thetissue contacting and/or penetration structures score the obstructivematerial and produce fissures and discontinuities at the site ofintervention. Application of a diagnostic or therapeutic composition(s)to the disrupted tissue improves uptake of the composition(s).

According to another embodiment, tissue contacting and/or penetrationstructures may be provided on a supporting structure in a bristle-likeor brush-like arrangement that may be adjustable between a smallerdelivery condition and an enlarged treatment condition. Bristle-likecontacting and/or penetration structures may be mounted in a stationarycondition on a support structure, or they may be mounted for movement inrelation to their support structure. In one embodiment, for example,bristle-like structures are mounted for pivoting or rotation about theirattachment points on a support structure or, alternatively, singlepenetration structures or groups of penetration structures may bemovable with or without requiring movement of a support structure.

In one embodiment, the tissue contacting and/or penetration structuresmay be coated with therapeutic and/or diagnostic compositions that arereleased during contact with tissue. In another embodiment, therapeuticand/or diagnostic compositions may be infused through channels providedin or associated with the tissue contacting and/or penetrationstructures, or through other infusion ports provided in proximity to thestructures. The tissue contacting and/or penetration structures may berotated and/or translated during application of the therapeutic and/ordiagnostic composition(s), or they may be maintained in a stationarycondition.

Therapeutic and/or diagnostic composition delivery systems of thepresent invention may be integrated with various types of interventionaldevices. Tissue contacting and/or penetration structures may beprovided, for example, on an inflatable device such as a balloon. In oneembodiment, the delivery systems disclosed herein are integrated with aninterventional catheter comprising a distally located material removalassembly operably connected to a rotatable drive shaft and associatedwith a catheter assembly providing lumen(s) for aspiration and/orinfusion, and suitable drive and control systems. Many types ofinterventional devices, including atherectomy and thrombectomy devices,tissue ablation devices, and the like, may incorporate delivery systemsof the present invention, such as an inflatable device and/or tissuecontacting and/or penetration structures for the delivery of atherapeutic and/or diagnostic composition.

These and additional features of the present invention and the manner ofobtaining them will become apparent, and the invention will be bestunderstood, by reference to the following more detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic diagram illustrating a side view of aninflatable structure having infusion ports and tissue contactingsurfaces adapted to produce discontinuities in tissue when the balloonis inflated.

FIG. 2 shows a schematic diagram illustrating a side view of the workinghead of an interventional catheter having a cutter assembly with tissuepenetration structures associated with the cutter assembly.

FIG. 3 shows a schematic diagram illustrating a side view of aninterventional catheter assembly of the present invention incorporatinga working head having a cutter assembly for removal of material from ablood vessel lumen, a brush-like element having bristles for contactingtissue at the interventional site, and infusion ports for infusion of atherapeutic composition.

DETAILED DESCRIPTION

As outlined above, the present invention provides systems and methodsfor delivery of therapeutic and/or diagnostic compositions to a site ofintervention. Delivery of therapeutic and/or diagnostic composition(s)using methods and structures of the present invention may be effectivelycombined with interventional procedures and devices for displacing orremoving unwanted material from a treatment site in a body lumen, suchas balloon angioplasty and/or stent placement procedures and devices,with atherectomy and thrombectomy procedures and devices, and with othermaterial removal and lumen enlarging procedures and devices.

Body lumens and cavities in which such systems and methods may beeffectively employed include blood vessels and vascular cavities,gastrointestinal cavities, lumens or cavities in male and femalereproductive organs, other fluid cavities such as gas exchange cavities,nasal and sinus cavities, and the like. The lumen or cavity may be agenerally tubular-shaped structure, such as blood vessel, including butnot limited to, peripheral arteries or blood vessels, or another lumenstructure, such as a ureter, a fallopian tube, a nasal passageway, andother tubular passageways. For example, systems disclosed herein may beused for removing undesired material from, and for deliveringtherapeutic and/or diagnostic compositions to, native blood vessels suchas native coronary, renal, cranial, peripheral and other blood vessels,artificial or grafted vessels such as saphenous vein grafts, and thelike. The body cavity may be within, or in proximity to, an organ, suchas a kidney, gall bladder, lung, or the like, or the body cavity mayform part of another system, such as a lymph node, spinal canal, etc.The disclosed systems are generally used with mammalian subjects,particularly human patients. The undesired material that is removed ordisplaced using the systems disclosed herein may be disease materialsuch as atherosclerotic plaque, calcified plaque, thrombus, gallstones,a valve or portion thereof, and the like.

According to some embodiments, methods and systems for deliveringtherapeutic and/or diagnostic composition(s) are used in combinationwith methods and systems for creating and enlarging openings inobstructed or partially obstructed lumens or cavities using angioplastictechniques, with or without the placement of implantable devices such asstents, including drug-eluting stents. Angioplastic techniques andsystems, implantable devices such as stents and drug-eluting stents arewell known in the art.

According to alternative embodiments, methods and systems for deliveringtherapeutic and/or diagnostic composition(s) are used in combinationwith methods and systems for removing material from a site ofintervention, such as various types of ablation systems using RF energy,high frequency ultrasound energy, lasers, high pressure fluids, thermalor electrical energy, and the like. These types of devices and systemsare well known in the art.

According to yet additional embodiments, methods and systems fordelivering therapeutic and/or diagnostic composition(s) are used incombination with methods and systems for removing material from a siteof intervention using an interventional catheter employing a coring orcutter mechanism, an abrasive mechanism, a scraping mechanism, anexcision mechanism, or the like. Material removal devices employing aninterventional catheter having a mechanism operating within a window ora bore in an interventional catheter such as a blade or a helical screwmay incorporate delivery of therapeutic and/or diagnostic composition(s)using methods and systems of the present invention. Interventionalcatheters employing rotatable and/or advanceable material removalassemblies having a coring or cutter mechanism, an abrasive mechanism, ascraping mechanism, an ablation mechanism or the like may alsoincorporate delivery of therapeutic and/or diagnostic composition(s)using methods and systems of the present invention. Illustrativeinterventional catheters are described, for example, in U.S. Pat. Nos.6,027,514, 6,241,744, 6,638,233, 6,447,525, 6,299,622, 6,629,953,6,623,496, 6,024,749, 6,638,288, 6,494,890, 6,001,112, 6,451,036,6,666,874, 5,779,721, 5,879,361, 6,569,147, 5,713,848, 6,545,775,6,936,025, 6,558,366, 6,984,239, 6,800,085, 5,484,433, 4,844,062 and5,836,946. The disclosures of these patent publications are incorporatedherein by reference in their entireties.

In certain embodiments, methods and systems for delivering therapeuticand/or diagnostic composition(s) are used in combination with methodsand systems for removing material from a site of intervention using aninterventional catheter employing an advanceable, rotatable distalcutter assembly. Advanceable, rotatable material removal systems thatthat may be effectively employed in the disclosed systems and methodsinclude, but are not limited to, systems using differential cuttingblades to remove unwanted material, such as those described in U.S. Pat.Nos. 6,565,588, 6,818,001 and 7,344,546, as well as U.S. PatentPublication No. US 2008/0103446, the disclosures of which areincorporated by reference herein in their entireties. In general, thesetypes of interventional catheters incorporate a rotatable andtranslatable material removal cutter assembly, referred to herein as a“cutter”, “cutter assembly” or “operating head” at their distal ends. Insome embodiments, the cutter assembly is operably connected to arotatable and axially translatable drive shaft and catheter system,drive system(s) and control system(s), and comprises at least onedistally located cutting or abrading surface, or blade.

As used herein, “proximal” refers to a direction toward the systemcontrols and the operator along the path of the drive shaft and cathetersystem, and “distal” refers to the direction away from the systemcontrols and the operator along the path of the drive shaft and cathetersystem toward or beyond a terminal end of the cutter assembly. Ingeneral, interventional catheters employed in the systems and methodsdisclosed herein comprise a cutter assembly comprising at least onecutting surface positioned at or near the distal end of theinterventional catheter system.

Although the “cutting” surfaces or blades of the interventionalcatheters may be sharp and may actually “cut” material at the targetsite, the term “cut” or “cutting,” as used herein, refers to cutting,scraping, ablating, macerating and otherwise breaking down undesiredmaterial into removable particles or smaller, removable, units ofmaterial. “Cutters,” “cutter assemblies,” “cutting surfaces” and“blades” likewise refer to structures for cutting, scraping, ablating,macerating and otherwise breaking down material into smaller pieces.Such surfaces may be provided with abrasive materials.

In certain embodiments, the cutting surface(s) or blade(s) operateaccording to the principles of differential cutting. The cuttingsurfaces or blades are preferably substantially rigid, with multipleblades preferably being radially symmetrical. Cutter assembliesdisclosed herein may comprise at least one cutting surface, andgenerally comprise a plurality of cutting blades. A cutter assembly mayhave fixed and/or adjustable blades. In one embodiment, a fixed bladecutter assembly is employed that comprises a plurality of cuttingblades. Although the cutting surfaces on the fixed blade cutter assemblyare not adjustable, the fixed blade cutter assembly may provide a rangeof cutting diameters as a consequence of a generally ovoid, or conical,external profile of the cutter assembly.

In another embodiment, a plurality of pivotable cutting blades areincorporated in an expandable cutter assembly that is navigable to theintervention site in a smaller diameter condition, adjusted to a largerdiameter condition at the target site during operation, and finallywithdrawn from the intervention site in a smaller diameter condition. Inanother aspect, cutter assemblies employed in the systems and methodsdisclosed herein incorporate both fixed cutting blades and pivotable, orexpandable, cutting blades in a dual, or composite, cutter assembly.

The drive shaft that conveys rotation and torque from a drive system tothe cutter assembly must be small enough and flexible enough to benavigated through small and tortuous passageways during navigation ofthe cutter assembly to the target removal site, and must have sufficientmechanical integrity to transfer high rotational and torque loads, andoperate in a high vacuum, aspirate withdrawal environment. Multi-filarhelical coils are used as drive shafts in many types of interventionalcatheters having a rotatable operating head.

In certain embodiments, interventional catheters employed in thedisclosed systems and methods include an aspiration system for removalof debris from the intervention site, generally via aspiration throughone or more material removal ports. Debris generated during a materialremoval operation is entrained in fluids (e.g. blood and/or infusate),and the aspirate fluid containing debris is removed by aspirationthrough the material removal port(s) and withdrawn through a sealedlumen of the interventional catheter. The sealed lumen is connectable toa vacuum source and aspirate collection system. Material removal portsmay be provided, for example, in the cutter assembly or proximal, but inproximity to, the cutter assembly. In one embodiment, one or moreaspiration port(s) may be disposed on or in proximity to the cutterassembly.

Liquid infusion may be provided in proximity to (e.g. at, distal to orproximal to) the cutter assembly in addition to, or alternatively to,aspiration. Infusion of liquids may be used to provide additional liquidvolume for removal of debris, and/or to deliver lubricating fluids,treatment or diagnostic compositions, contrast agents and the like.Infusion of fluids in proximity to the area of a material removaloperation may be desirable, as it tends to reduce the viscosity of thematerials being removed, thus facilitating removal through relativelysmall diameter lumens. In addition, infusion of liquids reduces thevolume of blood removed during a material removal operation, therebyreducing blood loss and allowing longer procedures if necessary. Inembodiments where guidewires are employed, liquid infusion may alsoreduce guidewire friction. In certain embodiments, a sealed lumen formedbetween the cutter assembly drive shaft and a catheter may alternativelyand selectively be used as an aspirate removal system and an infusionsystem. The sealed lumen may thus be selectively connectable to a vacuumsource and aspirate collection system for aspiration, and an infusionsource for infusion of liquids. Ports in or in proximity to the cutterassembly may thus be employed, selectively, as aspiration and infusionports. Fluid may also, or alternatively, be infused through ports in anouter catheter sheath positioned proximal to the cutter assembly.

As used herein, the term “therapeutic and/or diagnostic composition oragent” refers to any material employed for its therapeutic or diagnosticeffect(s) including naturally occurring and synthetic medicaments orchemicals, proteins, peptides, lipids, molecules or molecular fragments,genes, oligos, and other biological substances. Such compositions may bedelivered in solution or suspension or emulsion formulation, with asuitable carrier, and may incorporate additional components. Suchcompositions may also be delivered in a gel formulation or associatedwith a polymer or another matrix. Therapeutic and/or diagnosticcomposition(s) may alternatively be encapsulated in a liposome oranother structure or associated with a carrier such as a microsphere, abead, a nanoparticle or another particle, or the like.

Therapeutic compositions that may be effectively delivered using thedisclosed systems and methods include, but are not limited to,compositions that are able to inhibit or reduce or retard orsubstantially prevent restenosis and neointimal proliferation, promotehealing, promote tissue (e.g. blood vessel) health and structure, suchas thrombolytic compositions, anti-restenosis compositions,anti-aggregation compositions, anti-proliferation compositions andbioactive substances such as growth factors, wound healing compositions,etc.

More specifically, such therapeutic compositions include, but are notlimited to: anti-thrombogenic compositions, such as heparin, heparinderivatives, urokinase, and PPACK (dextrophenylalanine proline argininechloromethylketone); antioxidants, such as probucol and retinoic acid;angiogenic and anti-angiogenic compositions and factors; compositionsthat block smooth muscle cell proliferation, such as rapamycin,angiopeptin and monoclonal antibodies capable of blocking smooth musclecell proliferation; anti-inflammatory compositions such asdexamethasone, prednisolone, corticosterone, budesonide, estrogen,sulfasalazine, acetyl salicylic acid and mesalamine; calcium entryblockers such as verapamil, diltiazem and nifedipine;antineoplastic/antiproliferative/anti-mitotic compositions such aspaclitaxel, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin,tacrolimus, cyclosporine, cisplatin, vinblastine, vincristine,epothilones, endostatin, angiostatin and thymidine kinase inhibitors;immunosuppressants such as sirolimus (rapamycin); antimicrobials such astriclosan, cephalosporins, aminoglycosides, and nitorfurantoin;anesthetic compositions such as lidocaine, bupivacaine, and ropivacaine;nitric oxide (NO) donors such as lisidomine, molsidomine, L-arginine,NO-protein adducts, NO-carbohydrate adducts, polymeric or oligomeric NOadducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, RGDpeptide-containing compounds, heparin, antithrombin compounds, plateletreceptor antagonists, anti-thrombin antibodies, anti-platelet receptorantibodies, enoxaparin, hirudin, Warfarin, Dicumarol, aspirin,prostaglandin inhibitors, platelet inhibitors and antiplatelet factors;vascular cell growth promotors such as growth factors, growth factorreceptor antagonists, transcriptional activators and translationalpromotors; vascular cell growth inhibitors such as growth factorinhibitors, growth factor receptor antagonists, transcriptionalrepressors, translational repressors, replication inhibitors, inhibitoryantibodies, antibodies directed against growth factors, bi- (or multi-)functional molecules comprising a growth factor and a cytotoxin, and bi-(or multi-) functional molecules comprising an antibody and a cytotoxin;cholesterol-lowering compositions; vasodilating compositions;compositions which interfere with endogenous vascoactive mechanisms;survival genes which protect against cell death, such as anti-apoptoticBcl-2 family factors and Akt kinase; and combinations thereof.

Proteins that may be effectively delivered using the disclosed systemsand methods include angiogenic factors and other molecules able toinduce angiogenesis, including acidic and basic fibroblast growthfactors, vascular endothelial growth factor, HIF-1, epidermal growthfactor, transforming growth factor-alpha and -beta, platelet-derivedendothelial growth factor, platelet-derived growth factor, tumornecrosis factor-alpha, hepatocyte growth factor and insulin-like growthfactor; cell cycle inhibitors including CDK inhibitors; anti-restenosiscompositions, including p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkBand E2F decoys, thymidine kinase and combinations thereof; and othercompositions useful for interfering with cell proliferation, includingcompositions for treating malignancies. Protein fragments and peptidesmay be used. Polynucleotide sequences encoding such proteins andpeptides may also, or alternatively, be delivered to a treatment siteusing the disclosed systems and methods.

Other compositions that may be delivered using the present inventioninclude therapeutic polynucleotide sequences, such as sense andanti-sense, as well as modified and unmodified DNA and RNA molecules andfragments, DNA coding for an anti-sense RNA, or DNA coding for tRNA orrRNA to replace defective or deficient endogenous molecules, that have atherapeutic effect after being taken up by a cell.

The therapeutic and/or diagnostic composition may be formulated as acoating, in a solution or associated with a polymer or another type ofmatrix for infusion, and/or in a matrix or formulated on nanoparticlesor in or on beads (such as nanospheres or microspheres), liposomes, orother delayed or sustained release formulations. Methods for thepreparation of such formulations are well-known in the art. Varioustypes of biocompatible matrices may be used in coating formulations. Acombination of more than one therapeutic and/or diagnostic compositionmay be delivered to a desired treatment site. Different compositions maybe delivered to the treatment site at different times prior to, duringand/or following an interventional procedure.

In systems having a diagnostic and/or therapeutic composition deliverysystem incorporated with another interventional device, the integratedsystem may include an infusion manifold and at least one control featurefor supplying, and controlling administration of, one or morecompositions containing a therapeutic and/or diagnostic composition(s).Multiple chambers and/or infusion channels may be provided forsupplying, and controlling the administration of, multiple infusatecompositions. The compositions may be infused proximal or distal to anoperating head or another component of an interventional catheter,and/or through ports at various locations in the interventionalcatheter. Therapeutic and/or diagnostic compositions may be deliveredfollowing placement of the interventional catheter before, during and/orafter an interventional procedure.

In another embodiment, a therapeutic and/or diagnostic composition(s) isprovided as a coating on an inflatable device, such as a balloon- or aballoon-like device, which may be guided to an interventional site in anuninflated (e.g., collapsed) state and inflated or otherwise enlarged topresent a larger surface area at or near the site of intervention. Asurface of the inflated device preferably contacts tissue at the site ofintervention before, during or after an intervention. The inflatabledevice may have a generally cylindrical central region, and may have agenerally oval or oblong configuration overall. In many embodiments, theinflatable device is formed from a liquid and gas impermeable materialand may be constructed, for example, from thermoplastics, such aspolyurethane, polyvinyl chloride, polyethylene, polypropylene,polyamides and polyesters. Fluids are generally infused to an internalcavity in the inflatable device to inflate, or enlarge, the device atthe site of intervention.

Methods and materials for preparing drug-coated devices such as balloonsare known in the art and include, for example, those disclosed in U.S.Pat. Nos. 5,304,121 and 5,674,192, the disclosures of which are herebyincorporated by reference. In one aspect, the disclosed systems andmethods employ a balloon coated with a diagnostic or therapeuticcomposition, such as Paclitaxel, for example in an amount ofapproximately 1-10 (e.g. 3) mcg paclitaxel/mm² balloon surface. Suitableamounts of alternative diagnostic and therapeutic compositions may bedetermined using the knowledge of one of ordinary skill in the artand/or routine experimental protocols.

A coated inflatable device, such as a balloon, may be integrated with aninterventional catheter providing another interventional structure ormechanism for delivery therapeutic and/or diagnostic composition(s)according to methods and systems of the present invention. An inflatabledevice coated with a therapeutic and/or diagnostic composition and aninflation mechanism, such as a fluid delivery channel may, for example,be integrated with any of the interventional or material removal devicesreferred to above. In one embodiment, an inflatable device coated with atherapeutic and/or diagnostic composition may be integrated with anangioplasty system, for example. In another embodiment, an inflatabledevice coated with a therapeutic and/or diagnostic composition may beintegrated with an implantable device system such as a stent placementsystem. In yet another embodiment, an inflatable device coated with atherapeutic and/or diagnostic composition is integrated with a materialremoval system, such as an aspiration catheter, a plaque excision systemor a rotational atherectomy or thrombectomy system.

The coated inflatable device may be positioned proximal or distal to anoperating head of the interventional device during use, and may bemounted on, or integrated with, a dedicated inflation sheath associatedwith the interventional catheter. Alternatively, the coated inflatabledevice may share a fluid inflation lumen with the interventionalcatheter, with the fluid lumen serving as both an infusion and inflationlumen.

The coated inflatable device may be enlarged to contact the therapeuticand/or diagnostic composition(s) provided on its surface to the surfaceof tissue at or near the site of intervention before, during and/orafter an interventional operation. In one method, for example, theinterventional catheter is first employed to open a pathway at atreatment site in a body lumen or cavity, and the interventionalcatheter is subsequently repositioned so that the inflatable balloon islocated in proximity to the treatment site. The balloon is then inflated(or otherwise enlarged) so that at least part of the balloon's outersurface contacts the inner wall of the lumen or cavity, whereby thetherapeutic and/or diagnostic composition contacts the lumen wall. Theballoon may remain stationary during contact with the lumen or cavity,or it may be vibrated or otherwise moved against the inner wall of thelumen or cavity. The balloon may alternatively or additionally beemployed to deliver a therapeutic and/or diagnostic composition beforeuse of the interventional catheter, or the balloon may be employed afterremoval of the cutting assembly from the treatment site.

In another embodiment, which may be employed alternatively to or inconjunction with a coating on an inflatable device, the inflatabledevice may be constructed from a porous material or comprise one ormultiple pores. In this embodiment, a therapeutic and/or diagnosticcomposition may be formulated in and carried by the fluid used toinflate the balloon, such that the therapeutic and/or diagnosticcomposition “weeps” from the balloon when it is enlarged, and is therebydelivered to the treatment site. Multiple compositions may be deliveredto a site of intervention through a single inflatable device atdifferent times using this technique. Methods and materials for theconstructing such porous balloons are well known in the art and includethose described in U.S. Pat. Nos. 6,585,926, 5,318,531, 5,049,132,5,860,954 and 5,254,089, the disclosures of which are herebyincorporated by reference in their entireties.

Inflatable devices employed in the systems and methods disclosed hereinmay also, or alternatively, be provided with one or more tissuecontacting or penetration structures, such as cutting or abradingelement(s) on the exposed surface that act to cut or scrape or scoretissue, such as plaque, or produce fissures in the tissue duringcontact. Penetration or scoring of the tissue during or prior to contactwith a therapeutic and/or diagnostic composition assists in delivery anduptake of the therapeutic and/or diagnostic composition. The tissuepenetration structure(s) may be provided in the form of a rigid, orsemi-rigid, protrusion such as a pin or protuberance or blade element,or a wire or microneedle or the like, or may be provided as an abrasivematerial in the form of a particulate coating, such as diamond grit oranother type of abrasive material. The tissue penetration structure maybe provided with a coating comprising a therapeutic and/or diagnosticcomposition. A plurality of microneedles may be provided on the outersurface of the balloon, as disclosed for example in U.S. Pat. No.Publication No. US 2004/0098014, the disclosure of which is herebyincorporated by reference.

The tissue penetration structures may be substantially solid, or theymay have one or more channels or conduits through which a therapeuticand/or diagnostic composition may be delivered to a site ofintervention. Methods and materials for forming microneedles are wellknown to those of skill in the art and include, for example, thosedisclosed in U.S. Pat. Nos. 6,881,203, 6,331,266 and 6,503,231, thedisclosures of which are hereby incorporated by reference. FIG. 1illustrates one embodiment of an inflatable device of the presentinvention that may be used independently of an interventional device fordelivery of a diagnostic and/or therapeutic composition prior to, duringor following an intervention, or may be incorporated in aninterventional assembly. Inflatable device 10 is generally provided inassociation with and at or near the distal end of a catheter 12 and maybe translated to an interventional site on a guidewire 11. It isconveyed to the desired target site in a small diameter condition andinflated at the target site as is known in the art. The external surfaceof inflatable device 10 may incorporate a therapeutic compositioncoating, as is known in the art. The therapeutic composition coating maybe provided in a generally uniform distribution over the exposed surfaceof balloon 10, or a drug coating may be provided in a non-uniformdistribution, with higher concentrations of compositions, or differentcompositions, provided at different surface areas of balloon 10.

The external surface of balloon 10 may also incorporate one or aplurality of pores 14 for releasing a liquid formulation from aninternal space of the balloon. The pores may have substantially uniformsizes, as illustrated, or pores having different sizes may be provided.And, pores may be provided in a regular, radially arranged distribution,as shown in FIG. 1, or they may be provided in an irregular pattern overthe surface area of the balloon. Pores 14 are illustrated on thesubstantially cylindrical surfaces of balloon 10 in FIG. 1, but poresmay alternatively, or additionally, be provided on the tapered end wallsof balloon 10.

Balloon 10 additionally comprises a plurality of tissue contactingsurfaces 16 adapted to produce discontinuities or small fissures intissue when the balloon is inflated. Tissue contacting surfaces 16 maybe relatively sharp or relatively benign to tissue, and they may becoated with a diagnostic and/or therapeutic substance. They may beprovided in generally uniform sizes and in a regular arrangement, asillustrated in FIG. 1, or tissue contacting surfaces may havenon-uniform sizes and shapes, and they may be provided in an irregulararrangement over the surface area of the balloon. Tissue contactingsurfaces may comprise particulate materials, such as grit (e.g. diamondgrit) having various particle sizes.

The balloon may be delivered to a target intervention site for treatmentindependent of another intervention, or for treatment prior to, during,and/or following another interventional procedure. Upon delivery to thetarget site, the balloon is enlarged sufficiently so that at least aportion of the tissue contacting surfaces 16 contact tissue at thetarget intervention site. An infusate comprising a diagnostic and/ortherapeutic composition is preferably infused, e.g. through ports 14,during or following contacting of the tissue contacting surfaces withtissue at the target site. The balloon may be maintained in a generallystationary condition during treatment, or it may be translated orrotated or oscillated or vibrated or otherwise moved during treatment toenhance contacting of surfaces 16 with tissue at the site and to promoteuptake, but tissue at the site, of the diagnostic and/or therapeuticcomposition(s). Multiple compositions may be infused, sequentially orsimultaneously. The balloon is deflated and withdrawn from the sitefollowing the desired treatment.

In another embodiment, illustrated in FIG. 2, tissue penetrationstructures may be mounted on or associated with one or more componentsof an interventional device, such as one or more blades of a cutterassembly. FIG. 2 illustrates an exemplary interventional catheter 20mounted for axial translation on guidewire 21 and comprising a distaloperating head 22 having multiple, radially arranged cutter blades orsurfaces 25 and multiple ports 23. Tissue penetration structures 24 aremounted on blade surfaces 26 proximal to distal operating head 22. Thetissue penetration structures 24 score tissue, or produce fissures inthe tissue, as the interventional device is moved (e.g., rotated and/ortranslated) at the site of the intervention. The tissue penetrationstructures may be coated with a therapeutic and/or diagnosticcomposition, as described above, or they may be used in conjunction withan infusion system or an inflatable device for placing the therapeuticand/or diagnostic composition(s) at the site of intervention during orfollowing treatment of tissue. The tissue penetration structures may bemounted in a permanent and/or stationary condition, or they may bemounted for retraction during placement at or withdrawal from the siteof intervention.

The tissue penetration structures mounted on or associated with acomponent of an interventional device, such as a cutter assembly, may beprovided as serrated portions and/or abrasive or cutting structures,such as fine wires or comb-like structure(s). In one embodiment, forexample, wires or comb-like structures may be mounted to or associatedwith surfaces of blades forming a cutter assembly of an interventionalcatheter. In general, the wires or comb-like structures are oriented atan angle to, and generally transverse with respect to, the surface of ablade or another interventional catheter structure and project at leasta small distance from the peripheral edge of the blade or the otherstructure. As the blades are rotated and/or translated, the serrationsand/or abrasive elements (e.g., wires or comb-like structures) createfissures or discontinuities in the tissue located on the lumen wall atthe site of the intervention. These fissures improve penetration oftherapeutic and/or diagnostic compositions, such as anti-restenoticdrugs, that may be administered via infusion (e.g., through anintegrated infusion or through a separate infusion system) or using aninflatable device, such as a coated balloon as described above. Suchcompositions may be delivered either prior to, simultaneously with, orsubsequent to, operation of the cutting assembly.

Interventional catheters having abrasive elements and/or tissuepenetration structures may be employed in combination with drug-coatedand/or porous inflatable balloons, as detailed above, to improvedelivery of therapeutic and/or diagnostic compositions to tissue at thesite of intervention. An occluding balloon may also, or alternatively,be deployed distally to the site of intervention and the operating headof an interventional catheter system to retain a therapeutic and/ordiagnostic composition in the treatment area for a sufficient time foruptake of the composition. A distal occluding balloon may, for example,be provided on a guidewire. Examples of occluding balloons that beeffectively employed in the present systems and methods include thosedescribed in U.S. Pat. No. 4,790,813, the disclosure of which isincorporated by reference herein in its entirety.

In yet a further embodiment, a brush-like element comprising a number ofbristle-like structures capable of scoring or producing fissures intissue such as plaque, deposited on the inner wall of a vessel lumen,may be used to improve penetration of a therapeutic and/or diagnosticcomposition in tissue. The brush-like element(s) may be provided on, orintegrated with, an interventional catheter, or it may be provided as aseparate device and used independently from operation of aninterventional catheter. In use, the bristle-like structures contacttissue at a site of intervention before and/or after use of aninterventional catheter or delivery of a therapeutic and/or diagnosticcomposition, or may be left in place at a desired site for a period oftime to maximize the therapeutic effect. The brush-like element may beused to treat tissue, for example, prior to infusion of a diagnosticand/or therapeutic composition to improve uptake of the composition(s)by the treated tissue.

The bristle-like structures preferably have a stiffness sufficient toscore tissue as they are moved (e.g., rotated and/or translated) withrespect to the tissue. They may be provided with an abrasive material ontheir outer surface, and/or they may have sharp edges. The bristle-likestructures may be coated with a therapeutic composition, such aspaclitaxel or rapamycin, to improve penetration of the therapeuticcomposition in tissue at the site of intervention and thereby increasethe therapeutic effect. Alternatively, the bristle-like structures maybe hollow, or may be provided with infusion channels, and a therapeuticand/or diagnostic composition may be infused through the bristle-likestructures when they are positioned at a desired site, or duringmovement of the bristle-like structures at the site. In one embodiment,the bristles may be constructed from microporous fibers and channelsprovided in the fibers may be in communication with a source ofinfusate. Microporous fibers having, for example, an inner diameter of0.001 inch and an outer diameter of 0.003 inch are suitable bristle-likestructures.

In one embodiment, the bristle-like structures extend generally radiallyfrom, and are mounted in a fixed, stationary condition on a supportingstructure. The supporting structure may comprise at least part of theouter circumference of the catheter, or it may comprise a structureseparate from a catheter. In other embodiments, the bristles rotate,reciprocate and/or pivot at their attachment points. In one embodiment,the bristles of the brush-like element extend from the outer surface ofthe catheter at an angle that is approximately 90° to the longitudinalaxis of the catheter. In other embodiments, the angle between thebristles and the longitudinal axis of the catheter is less than 90° withthe tips of the bristles pointing in either a generally proximal ordistal direction, and the bristles are able to pivot along a limited,generally longitudinal path. The bristles are of a sufficient length tocontact the deposited material whereby, as the catheter is moved eitherproximally or distally, the tips of the bristles are forced into theplaque and moved from a generally proximal or distal orientation, to agenerally vertical orientation and finally to a generally distal orproximal orientation.

In one embodiment, illustrated schematically in FIG. 3, a brush-likeelement 42 is provided on an interventional catheter assembly 40generally proximal to a cutting assembly 44, with the bristles initiallylying in a generally proximal orientation. The cutting assembly may beoperated, first, to cut or debulk material, such as plaque, deposited onthe inside of a body lumen. Following a debulking operation, thecatheter may be moved distally to position the brush-like element 42 inproximity to the portion of the vessel where the intervention tookplace, and near exposed tissue surfaces. The catheter may then betranslated in a proximal direction, whereby the bristles penetratetissue at the site, delivering a treatment composition to the exposedtissue. Employing an interventional catheter having both a cuttingassembly and a brush-like element means that both plaque removal anddelivery of a therapeutic composition may be achieved by placement of asingle catheter in the vessel, resulting in improved time and costefficiency compared to the use of two catheters and reducing risk to thepatient.

The interventional catheter assembly illustrated schematically in FIG. 3additionally comprises a plurality of infusion ports 45 provided in aninflatable member 46 mounted on interventional catheter 40 proximally ofthe brush-like element 42. Various compositions may be infused throughinflatable member 46 prior to or during an atherectomy or thrombectomyprocedure, and prior to or during subsequent treatment using thebrush-like element. Employing an interventional catheter having acutting assembly, a brush-like member and one or more infusion systemsprovides plaque removal and effective delivery of a diagnostic and/ortherapeutic composition with placement of a single catheter in thevessel, resulting in improved time and cost efficiency compared to theuse of two catheters and reducing risk to the patient.

While the present invention has been described with reference tospecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. Many alternative embodiments are disclosed, many of which maybe combined in methods and systems of the present invention. Inaddition, many modifications may be made to adapt a particularsituation, material, composition of matter, method, method step orsteps, for use in practicing the present invention. All suchmodifications are intended to be within the scope of the claims.

All of the publications, patent applications, and patents cited in thisapplication are herein incorporated by reference in their entireties tothe same extent as if each individual publication, patent application orpatent was specifically and individually indicated to be incorporated byreference in its entirety.

I claim:
 1. An interventional device comprising: (a) a catheter; (b) atleast one of an angioplastic device, an operating head for removal ofmaterial, and a delivery device for placement of implantable devicespositioned at or near a distal end of the catheter; (c) a surfacepositioned at or near a distal end of the catheter configured forcontacting tissue at a site of intervention; and (d) a compositioncomprising a therapeutic and/or diagnostic composition associated withthe surface providing release or uptake of the composition when thesurface contacts tissue at the site of intervention.
 2. Theinterventional device of claim 1, comprising an operating head forremoval of material, wherein the operating head is selected from thegroup consisting of: a cutter assembly, a scraping mechanism, a coringmechanism, a helical screw mechanism, a laser ablative mechanism, a highfrequency ultrasound source, a radio frequency (RF) source, a thermalsource, and an electrical source.
 3. The interventional device of claim1, comprising a delivery device for placement of implantable stents. 4.The interventional device of claim 1, wherein the surface is on aninflatable device positioned at or near a distal end of the catheter. 5.The interventional device of claim 4, wherein the inflatable deviceincorporates structures on its outer surface selected from the groupconsisting of: blades, pins, surface protuberances, abrasives, roughedges and microneedles.
 6. The interventional device of claim 1,additionally comprising an inflatable device positioned at or near adistal end of the catheter incorporating pores or ports that, when theinflatable device is inflated, allow passage of fluids.
 7. Theinterventional device of claim 1, additionally comprising at least onematerial removal port at or near a distal end of the catheter foraspirating fluid containing debris from an intervention site.
 8. Theinterventional device of claim 1, wherein the catheter comprises asealed infusion lumen and a sealed aspiration lumen.
 9. Aninterventional device comprising: (a) a catheter having an infusionlumen connected to an infusate source; (b) at least one of anangioplastic device, an operating head for removal of material, and adelivery device for placement of implantable devices positioned at ornear a distal end of the catheter; and (c) an inflatable device havingpores or ports allowing passage of fluids containing therapeutic and/ordiagnostic substances positioned at or near a distal end of thecatheter.
 10. The interventional device of claim 9, comprising anoperating head for removal of material, wherein the operating head isselected from the group consisting of: a cutter assembly, a scrapingmechanism, a coring mechanism, a helical screw mechanism, a laserablative mechanism, a high frequency ultrasound source, a radiofrequency (RF) source, a thermal source, and an electrical source. 11.The interventional device of claim 9, comprising a delivery device forplacement of implantable stents.
 12. The interventional device of claim9, wherein the catheter comprises a sealed infusion lumen and a sealedaspiration lumen.
 13. A method for administering a therapeutic and/ordiagnostic composition to an internal lumen or cavity prior to, duringor following an interventional procedure, comprising: (a) delivering theworking head of an interventional catheter to the site of aninterventional procedure; (b) operating the working head to at leastpartially displace or remove an obstruction from an internal lumen orcavity; (c) contacting a surface mounted on a component of theinterventional catheter to tissue at the site of the interventionalprocedure prior to, during or following operation of the working head,wherein the surface comprises a therapeutic and/or diagnosticcomposition.
 14. The method of claim 13, wherein the interventional siteis selected from the group consisting of: blood vessels and vascularcavities, gastrointestinal cavities, lumens or cavities in male andfemale reproductive organs and the urinary tract, gas exchange cavities,and nasal and sinus cavities.
 15. The method of claim 13, wherein theinterventional procedure involves enlarging an opening in an obstructedor partially obstructed lumen or cavity.
 16. The method of claim 13,wherein the surface is provided on an inflatable device.
 17. The methodof claim 16, wherein the inflatable device additionally has ports forinfusion of the therapeutic and/or diagnostic composition.
 18. Themethod of claim 13, additionally comprising rotating and/or translatingand/or vibrating the surface during contacting of the surface to tissue.19. The method of claim 13, wherein the therapeutic and/or diagnosticcomposition comprises a composition selected from the group consistingof: thrombolytic compositions; anti-restenosis compositions;anti-aggregation compositions; anti-proliferation compositions; growthfactors; wound healing compositions; anti-thrombogenic compositions;antioxidants; angiogenic compositions and factors; anti-angiogeniccompositions and factors; compositions that block smooth muscle cellproliferation; anti-inflammatory compositions; calcium entry blockers;antineoplastic compositions; antimitotic compositions; immunosuppressantcompositions; antimicrobial compositions; anesthetic compositions;nitric oxide donors; anti-coagulants; vascular cell growth promoters;vascular cell growth inhibitors; cholesterol-lowering compositions;vasodilating compositions; compositions that interfere with endogenousvasoactive mechanisms; survival genes; and polynucleotide sequences. 20.The method of claim 13, wherein the therapeutic and/or diagnosticcomposition comprises a composition selected from the group consistingof: anti-thrombogenic compositions, heparin, heparin derivatives,urokinase, PPACK (dextrophenylalanine proline argininechloromethylketone), antioxidants, probucol, retinoic acid; angiogenicand anti-angiogenic compositions and factors, compositions that blocksmooth muscle cell proliferation, rapamycin, angiopeptin, monoclonalantibodies capable of blocking smooth muscle cell proliferation,anti-inflammatory compositions, dexamethasone, prednisolone,corticosterone, budesonide, estrogen, sulfasalazine, acetyl salicylicacid, mesalamine, calcium entry blockers, verapamil, diltiazem,nifedipine, antineoplastic/antiproliferative/anti-mitotic compositions,paclitaxel, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin,tacrolimus, cyclosporine, cisplatin, vinblastine, vincristine,epothilones, endostatin, angiostatin, thymidine kinase inhibitors.Immunosuppressants, sirolimus (rapamycin), antimicrobials, triclosan,cephalosporins, aminoglycosides, nitorfurantoin, anestheticcompositions, lidocaine, bupivacaine, ropivacaine, nitric oxide (NO)donors, lisidomine, molsidomine, L-arginine, NO-protein adducts,NO-carbohydrate adducts, polymeric or oligomeric NO adducts,anti-coagulants, D-Phe-Pro-Arg chloromethyl ketone, RGDpeptide-containing compounds, antithrombin compounds, platelet receptorantagonists, anti-thrombin antibodies, anti-platelet receptorantibodies, enoxaparin, hirudin, Warfarin, Dicumarol, aspirin,prostaglandin inhibitors, platelet inhibitors, antiplatelet factors,vascular cell growth promotors, growth factors, growth factor receptorantagonists, transcriptional activators and translational promotors,vascular cell growth inhibitors, growth factor inhibitors, growth factorreceptor antagonists, transcriptional repressors, translationalrepressors, replication inhibitors, inhibitory antibodies, antibodiesdirected against growth factors, bi- (or multi-) functional moleculescomprising a growth factor and a cytotoxin, bi- (or multi-) functionalmolecules comprising an antibody and a cytotoxin, cholesterol-loweringcompositions, vasodilating compositions, compositions which interferewith endogenous vascoactive mechanisms, survival genes which protectagainst cell death, anti-apoptotic Bcl-2 family factors, Akt kinase, andcombinations thereof.
 21. The method of claim 13, wherein thetherapeutic and/or diagnostic composition comprises a proteinaceouscomposition selected from the group consisting of: angiogenic factorsand other molecules able to induce angiogenesis, acidic and basicfibroblast growth factors, vascular endothelial growth factor, HIF-1,epidermal growth factor, transforming growth factor-alpha and -beta,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor-alpha, hepatocyte growth factor,insulin-like growth factor, cell cycle inhibitors, CDK inhibitors,anti-restenosis compositions, p15, p16, p18, p19, p21, p27, p53, p57,Rb, nFkB and E2F decoys, thymidine kinase, combinations thereof, proteinfragments and peptides thereof, and polynucleotide sequences encodingrecited proteins, peptides and fragments.
 22. The method of claim 13,wherein the therapeutic and/or diagnostic composition comprises acomposition selected from the group consisting of: therapeuticpolynucleotide sequences, such as sense and anti-sense, as well asmodified and unmodified DNA and RNA molecules and fragments, DNA codingfor an anti-sense RNA, or DNA coding for tRNA or rRNA to replacedefective or deficient endogenous molecules, that have a therapeuticeffect after being taken up by a cell.